US2024002388A1PendingUtilityA1
Pyrimidinone compounds and uses thereof
Est. expiryAug 18, 2040(~14.1 yrs left)· nominal 20-yr term from priority
A61P 37/00A61P 35/00A61P 25/00A61P 19/02C07D 487/04A61K 45/06C07D 471/04C07D 413/12C07D 239/47C07D 403/12A61K 31/513Y02P20/55C07D 239/36A61K 31/519A61P 29/00
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Claims
Abstract
It relates to pyrimidinone compounds and uses thereof. In particular, it relates to pyrimidinone compounds of formula (I), and the pharmaceutical compositions, the preparing methods and the uses thereof, wherein the variables are as defined in the description.
Claims
exact text as granted — not AI-modified1 . A compound of formula (I):
or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein
R 1 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano-substituted C 1-6 alkyl, —(C 1-6 alkylene) n -C 3-6 cycloalkyl, —(C 1-6 alkylene) n -phenyl, —(C 1-6 alkylene) n -4-6 membered heterocyclyl or —(C 1-6 alkylene) n -5-6 membered heteroaryl; wherein the C 3-6 cycloalkyl, phenyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl are each optionally substituted with one or more groups independently chosen from: halogen, —CN, —OH, —NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, —O(C 1-6 alkyl), —O(C 1-6 haloalkyl), —NH(C 1-6 alkyl) and —N(C 1-6 alkyl) 2 ;
R 2 is hydrogen, halogen, —CN, —NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, —O(C 1-6 alkyl), —O(C 1-6 haloalkyl), —NH(C 1-6 alkyl) or —N(C 1-6 alkyl) 2 ;
Z is O, NR 3 or CR 4 R 5 ;
R 3 is hydrogen or C 1-6 alkyl;
R 4 and R 5 are each independently chosen from: hydrogen, halogen, —CN, —OH, C 1-6 alkyl, C 1-6 haloalkyl, —O(C 1-6 alkyl), —O(C 1-6 haloalkyl) and C 3-6 cycloalkyl;
is phenyl or 5-6 membered heteroaryl, each of which is optionally substituted with one or more groups independently chosen from: halogen, —CN, —OH, —NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, —O(C 1-6 alkyl), —O(C 1-6 haloalkyl), —NH(C 1-6 alkyl) and —N(C 1-6 alkyl) 2 ;
is 5-12 membered heteroaryl, which is optionally substituted with one or more groups independently chosen from: halogen, —CN, —OH, oxo, —NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, —O(C 1-6 alkyl), —O(C 1-6 haloalkyl), —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —(C 1-6 alkylene) n -C 3-6 cycloalkyl, —(C 1-6 alkylene) n -phenyl, —(C 1-6 alkylene) n -4-6 membered heterocyclyl and —(C 1-6 alkylene) n -5-6 membered heteroaryl; wherein the phenyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl are each optionally substituted with one or more groups independently chosen from: halogen, —CN, —OH, —NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, —O(C 1-6 alkyl), —O(C 1-6 haloalkyl), —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 and C 3-6 cycloalkyl;
n is 0 or 1;
and p is 0 or 1.
2 . (canceled)
3 . The compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof according to claim 1 , wherein R 1 is C 1-6 alkyl, C 1-6 haloalkyl, cyano-substituted C 1-6 alkyl, —(C 1-6 alkylene) n -C 3-6 cycloalkyl or —(C 1-6 alkylene) n -4-6 membered heterocyclyl; wherein the C 3-6 cycloalkyl and 4-6 membered heterocyclyl are each optionally substituted with one or more groups independently chosen from: halogen and C 1-6 alkyl.
4 . The compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof according to claim 3 , wherein R 1 is C 1-6 alkyl.
5 . The compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof according to claim 3 , wherein R 1 is —(C 1-6 alkylene) n -C 3-6 cycloalkyl, wherein the C 3-6 cycloalkyl is optionally substituted with one or more halogen, and n is 0 or 1; or R 1 is 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is oxetanyl, tetrahydrofuranyl or tetrahydropyranyl.
6 . The compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof according to claim 1 , wherein R 2 is hydrogen, —NH 2 or C 1-6 alkyl.
7 . The compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof according to claim 1 , wherein p is 0, and Z is CH 2 .
8 . The compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof according to claim 1 , wherein
is phenyl or pyridyl, each of which is optionally substituted with one or more groups independently chosen from: halogen, C 1-6 alkyl, and C 1-6 haloalkyl.
9 . The compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof according to claim 1 , wherein
is 5-9 membered heteroaryl, which is optionally substituted with one or more groups independently chosen from: halogen, C 1-6 alkyl, —(C 1-6 alkylene) n -C 3-6 cycloalkyl, —(C 1-6 alkylene) n -phenyl, —(C 1-6 alkylene) n -4-6 membered heterocyclyl and —(C 1-6 alkylene) n -5-6 membered heteroaryl; and wherein the phenyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl are each optionally substituted with one or more halogen.
10 . The compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof according to claim 1 , wherein the compound of formula (I) is the compound of formula (I-1):
wherein
R 1 is C 1-6 alkyl, C 1-6 haloalkyl, cyano-substituted C 1-6 alkyl, —(C 1-6 alkylene) n -C 3-6 cycloalkyl or —(C 1-6 alkylene) n -4-6 membered heterocyclyl; wherein the C 3-6 cycloalkyl and 4-6 membered heterocyclyl are each optionally substituted with one or more groups independently chosen from: halogen and C 1-6 alkyl;
R 2 is hydrogen, —NH 2 or C 1-6 alkyl;
is 5-9 membered heteroaryl, which is optionally substituted with one or more groups independently chosen from: halogen, C 1-6 alkyl, —(C 1-6 alkylene) n -C 3-6 cycloalkyl, —(C 1-6 alkylene) n -phenyl, —(C 1-6 alkylene) n -4-6 membered heterocyclyl and —(C 1-6 alkylene) n -5-6 membered heteroaryl; wherein the phenyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl are each optionally substituted with one or more halogen;
and n is 0 or 1.
11 . The compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof according to claim 1 , wherein
is triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrimidyl, pyrazolopyrimidyl, pyrazolopyridyl or dihydropyrrolotriazolyl, each of which is optionally substituted with one or more groups independently chosen from: halogen, C 1-6 alkyl, —(C 1-6 alkylene) n -C 3-6 cycloalkyl, —(C 1-6 alkylene) n -phenyl, —(C 1-6 alkylene) n -4-6 membered heterocyclyl and —(C 1-6 alkylene) n -5-6 membered heteroaryl; wherein the phenyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl are each optionally substituted with one or more halogen.
12 . The compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof according to claim 11 , wherein
is chosen from
each of which is optionally substituted with one or more groups independently chosen from: halogen, C 1-6 alkyl, —(C 1-6 alkylene) n -C 3-6 cycloalkyl, —(C 1-6 alkylene) n -phenyl, —(C 1-6 alkylene) n -4-6 membered heterocyclyl and —(C 1-6 alkylene) n -5-6 membered heteroaryl; wherein the phenyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl are each optionally substituted with one or more halogen.
13 . The compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof according to claim 12 , wherein
which is optionally substituted with one or more groups independently chosen from: C 1-6 alkyl, —(C 1-6 alkylene) n -C 3-6 cycloalkyl, —(C 1-6 alkylene) n -phenyl, —(C 1-6 alkylene) n -4-6 membered heterocyclyl and —(C 1-6 alkylene) n -5-6 membered heteroaryl; and wherein the C 3-6 cycloalkyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl are each optionally substituted with one or more halogen, and n is 0 or 1.
14 . The compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof according to claim 13 , wherein
which is optionally substituted with one or more groups independently chosen from: C 1-6 alkyl;
or
which is optionally substituted with one or more groups independently chosen from: —(C 1-6 alkylene) n -C 3-6 cycloalkyl, wherein n is 0 or 1; wherein the C 3-6 cycloalkyl is optionally substituted with one or more halogen;
or
which is optionally substituted with one or more groups independently chosen from: —(C 1-6 alkylene) n -phenyl, wherein n is 0 or 1;
or
which is optionally substituted with one or more groups independently chosen from: 4-6 membered heterocyclyl; wherein the 4-6 membered heterocyclyl is oxetanyl;
or
which is optionally substituted with one or more groups independently chosen from: 5-6 membered heteroaryl; wherein the 5-6 membered heteroaryl is pyridyl.
15 . The compound of formula (I), or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound of formula (I) is chosen from Compounds 1-19, 22-48 and 53-95:
Compound
No.
Structure
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15 and 16
and
17
18
19
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
53 and 54
and
55 and 56
and
57 and 58
and
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80 and 81
and
82 and 83
and
84 and 85
and
86
87 and 88
and
89 and 90
and
91
92
93
94
95
16 . A pharmaceutical composition, comprising the compound or a pharmaceutically acceptable salt thereof according to claim 1 , and optionally comprising a pharmaceutically acceptable carrier.
17 . A method of in vivo or in vitro inhibiting the activity of RIPK1, comprising contacting RIPK1 with an effective amount of the compound or a pharmaceutically acceptable salt thereof according to claim 1 .
18 . A method of treating a disease partially or completely mediated by RIPK1 in a subject, comprising administering to the subject an effective amount of the compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the disease is chosen from an autoimmune disease, an inflammatory disease, a neurodegenerative disease, and cancer.
19 . (canceled)
20 . (canceled)
21 . (canceled)
22 . (canceled)
23 . (canceled)
24 . (canceled)
25 . A pharmaceutical combination, comprising the compound or a pharmaceutically acceptable salt thereof according to claim 1 , and at least one additional therapeutic agent.
26 . The pharmaceutical combination according to claim 25 , wherein the therapeutic agent is an anti-inflammatory agent or an anti-neoplastic agent; and the anti-neoplastic agent is chosen from a radiotherapeutic agent, a chemotherapeutic agent, an immunotherapeutic agent and a targeted therapeutic agent.Join the waitlist — get patent alerts
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